Methadone for Mechanical Ventilation

(IMPACTOR Trial)

Overseen By Elizabeth Vidales

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: The University of Texas Health Science Center, Houston

Must be taking: Fentanyl, Hydromorphone

Must not be taking: Schedule II narcotics

Disqualifiers: Opioid abuse, Spinal injury, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Duration of hospital stay

80 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the effect of methadone on the duration on mechanical ventilation in critically ill patients receiving more than 72 hours of mechanical ventilation (MV) by comparing the number of ventilator free days from enrollment to the time of discharge, to assess the safety of methadone administration in critically ill patients while in the hospital and to determine hospital length of stay from the time of enrollment to the time of discharge

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those who have been on schedule II narcotics for more than 6 months or on other analgesic infusions besides Fentanyl or Hydromorphone.

What data supports the effectiveness of the drug methadone for mechanical ventilation?

Research suggests that using methadone can help reduce the time it takes to wean patients off mechanical ventilation, as it may help manage withdrawal symptoms from other opioids and improve breathing trials. ^{1 2 3 4 5}

Is methadone generally safe for use in humans?

Methadone is generally safe when used at lower doses, but there are risks, especially with high doses or when combined with other drugs. It can cause heart rhythm issues and has been linked to deaths, particularly when doses are increased too quickly or when used with other central nervous system depressants like benzodiazepines. ^{1 2 6 7 8}

How is the drug methadone unique for patients on mechanical ventilation?

Methadone is unique because it is a long-acting opioid that can help reduce the time needed to wean patients off mechanical ventilation by providing stable pain relief and sedation, potentially avoiding withdrawal symptoms that can occur with other opioids. ^{1 2 3 6 9}

Research Team

Pascal Kingah, MD, MPH

Principal Investigator

The University of Texas Health Science Center, Houston

Eligibility Criteria

This trial is for critically ill patients who've been on mechanical ventilation and opioid pain meds like Fentanyl or Hydromorphone for over 72 hours, are stable, and have had unsuccessful breathing trials. It's not for those with a history of opioid abuse, chronic narcotic use, certain heart or liver conditions, neuromuscular diseases, or without feeding tubes.

Inclusion Criteria

I have been on a breathing machine for more than 3 days.

My heart and blood pressure are stable.

I have been given Fentanyl or Hydromorphone for over 72 hours.

Exclusion Criteria

Patients with QTc increase of ≥60 milliseconds above the value of prior EKGs measured during current ICU admission

I have been on strong painkillers for more than 6 months before being admitted to the ICU.

I have severe liver disease and am not on warfarin with high INR and bilirubin levels.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive methadone or standard care while on mechanical ventilation

Duration of hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Methadone

Trial Overview The study tests if methadone can reduce the time critically ill patients need mechanical ventilation. Participants will either receive usual care or be given methadone. The main focus is to compare ventilator-free days from enrollment to discharge and assess safety and hospital stay length.

Participant Groups

Group I: Methadone group Experimental Treatment 1 Intervention

Group II: Non-Methadone group Active Control 1 Intervention

Methadone is already approved in United States, European Union, Canada, Japan, Switzerland for the following indications:

Approved in United States as Dolophine for:

• Pain management
• Opioid use disorder

Approved in European Union as Methadose for:

• Pain management
• Opioid dependence

Approved in Canada as Physeptone for:

• Pain management
• Opioid use disorder

Approved in Japan as Heptadon for:

• Pain management

Approved in Switzerland as Heptanon for:

• Pain management
• Opioid dependence

Who Is Running the Clinical Trial?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

Findings from Research

In a study of 52 cancer patients, rotating to methadone for pain management was effective, achieving adequate pain relief in 89% of patients within 3 days, particularly for those with mixed nociceptive-neuropathic pain.

The study suggests that using a fixed equianalgesic ratio of 10:1 for patients with a morphine-equivalent daily dose (MEDD) under 400 mg may be sufficient, indicating a tailored approach to opioid rotation can enhance pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone rotation for cancer pain: an observational study. Tan, C., Wong, JF., Yee, CM., et al.[2022]

A study of 39 patients undergoing opioid rotation from methadone to alternative opioids found that the mean dose ratio for oral methadone to oral morphine equivalent daily dose was 1:4.7, and for intravenous methadone, it was 1:13.5, indicating significant differences in potency between the two forms.

The research suggests that these new dose ratios can help clinicians switch patients to alternative opioids more safely, especially when managing side effects or inadequate pain control from methadone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Switching from methadone to a different opioid: what is the equianalgesic dose ratio? Walker, PW., Palla, S., Pei, BL., et al.[2018]

Methadone is a unique opioid that not only acts on mu receptors but also has effects on delta receptors and NMDA receptors, making it a complex option for pain management, especially in cases of uncontrolled pain or when other opioids cause toxicity.

While methadone can be safer at lower doses, there are significant risks associated with high doses, including prolonged QT interval and potential for serious heart issues, highlighting the need for more research through randomized controlled trials to better understand its safety and efficacy compared to other opioids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone for treatment of cancer pain. Bryson, J., Tamber, A., Seccareccia, D., et al.[2019]

Between 2001 and 2005, there were 206 reported methadone-associated deaths in Victoria, Australia, primarily due to drug toxicity, highlighting the risks associated with methadone use, especially when combined with other CNS depressants.

A significant number of deaths (25%) occurred within 14 days of starting opioid replacement therapy with methadone, often linked to high starting doses and rapid dose increases, suggesting that better management during the induction phase could help reduce mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of methadone deaths between 2001 and 2005 in Victoria, Australia. Pilgrim, JL., McDonough, M., Drummer, OH.[2013]

References

1. France pubmed.ncbi.nlm.nih.gov

Role of Methadone in Extracorporeal Membrane Oxygenation: Two Case Reports. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Methadone rotation for cancer pain: an observational study. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Switching from methadone to a different opioid: what is the equianalgesic dose ratio? [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Methadone for treatment of cancer pain. [2019]

7. France pubmed.ncbi.nlm.nih.gov

[Plasma assay of methadone enantiomers with high performance liquid chromatography]. [2019]

8. Ireland pubmed.ncbi.nlm.nih.gov

A review of methadone deaths between 2001 and 2005 in Victoria, Australia. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Methadone analgesia in the critically ill. [2018]